6020 The Journal of Neuroscience, April 15, 2015 35(15):6020 6027

Behavioral/Cognitive

Emotion Regulation and Trait Anxiety Are Predicted by the

Microstructure of Fibers between Amygdala and Prefrontal
Cortex
Annuschka Salima Eden,1 Jan Schreiber,4 X Alfred Anwander,4 X Katharina Keuper,1,3 Inga Laeger,2 Peter Zwanzger,2
Pienie Zwitserlood,5 X Harald Kugel,6 and Christian Dobel1,3
1

Institute for Biomagnetism and Biosignalanalysis and 2Department of Psychiatry, University Hospital, 48149 Munster, Germany, 3Otto Creutzfeldt Center
for Cognitive and Behavioural Neuroscience, 48149 Munster, Germany, 4Max Planck Institute for Human Cognitive and Brain Sciences, 04103 Leipzig,
Germany, 5Westfalische Wilhelms-Universitat, 48149 Munster, Germany, and 6Center of Radiology, Faculty of Medicine, 48149 Munster, Germany

Diffusion tensor imaging revealed that trait anxiety predicts the microstructural properties of a prespecified fiber tract between the
amygdala and the perigenual anterior cingulate cortex. Besides this particular pathway, it is likely that other pathways are also affected.
We investigated white matter differences in persons featuring an anxious or a nonanxious personality, taking into account all potential
pathway connections between amygdala and anxiety-related regions of the prefrontal cortex (PFC). Diffusion-weighted images, measures
of trait anxiety and of reappraisal use (an effective emotion-regulation style), were collected in 48 females. With probabilistic tractography, pathways between the amygdala and the dorsolateral PFC, dorsomedial PFC, ventromedial PFC, and orbitofrontal cortex (OFC) were
delineated. The resulting network showed a direct ventral connection between amygdala and PFC and a second limbic connection
following the fornix and the anterior limb of the internal capsule. Reappraisal use predicted the microstructure of pathways to all
calculated PFC regions in the left hemisphere, indicating stronger pathways for persons with high reappraisal use. Trait anxiety predicted
the microstructure in pathways to the ventromedial PFC and OFC, indexing weaker connections in trait-anxious persons. These effects
appeared in the right hemisphere, supporting lateralization and top-down inhibition theories of emotion processing. Whereas a specific
microstructure is associated with an anxious personality, a different structure subserves emotion regulation. Both are part of a broad
fiber tract network between amygdala and PFC.
Key words: amygdala; DTI; PFC; reappraisal use; top-down inhibition; trait anxiety

Introduction
The interplay between amygdala and prefrontal cortex (PFC) is
central to the regulation of emotions. Crucial components of this
interplay are top-down inhibition processes manifesting themselves in downregulation of the amygdala by medial PFC (mPFC;
Bishop, 2007). A greater functional connectivity between the
amygdala and the mPFC was reported in persons with low anxiety (Pezawas et al., 2005). Investigating fiber connections in white
matter, Kim and Whalen (2009) applied diffusion tensor imaging
(DTI) and found that trait anxiety, a stable tendency to respond
with anxiety, predicted the microstructure of a ventral amygdala
PFC pathway. Persons high in trait anxiety showed lower values
of fractional anisotropy (FA; Basser and Pierpaoli, 1996) on this

Received July 26, 2014; revised Jan. 31, 2015; accepted Feb. 3, 2015.
Author contributions: A.S.E., K.K., I.L., Pe.Z., Pi.Z., and C.D. designed research; A.S.E. and H.K. performed research;
J.S., A.A., H.K., and C.D. contributed unpublished reagents/analytic tools; A.S.E., J.S., and A.A. analyzed data; A.S.E.,
J.S., A.A., K.K., I.L., Pe.Z., Pi.Z., H.K., and C.D. wrote the paper.
This work was supported by the Interdisciplinary Center for Clinical Research (Grant Do3/021/10).
The authors declare no competing financial interests.
Correspondence should be addressed to Annuschka Salima Eden, Institute for Biomagnetism and Biosignalanalysis, Malmedyweg 15, 48143 Munster, Germany. E-mail: Annuschka.Eden@uni-muenster.de.
DOI:10.1523/JNEUROSCI.3659-14.2015
Copyright 2015 the authors 0270-6474/15/356020-08$15.00/0

tract to the perigenual anterior cingulate cortex, i.e., weaker connections. It is likely that a larger network of amygdalaPFC connections is affected in trait anxiety (for review, see Ray and Zald,
2012). Data by Kim and Whalen (2009) support the idea that
anxiety is associated with ineffective top-down inhibition. These
dysfunctional processes might be attributable to an attenuated
use of reappraisal, a coping strategy involving reinterpretation of
the emotional meaning of stimuli. Low reappraisal results in low
activity in PFC regions and in high amygdala activity (Ochsner et
al., 2002, 2004; Kim and Hamann, 2007). In women, the microstructural foundation for this interplay is related to the integrity
of white matter pathways between amygdala and PFC (Zuurbier
et al., 2013).
Anatomical knowledge about amygdalaPFC connections
mostly derives from primates. Because of close cytoarchitectural
homology between primates and humans (Petrides and Mackey,
2006; Jbabdi et al., 2013), a transfer of findings seems reasonable
but awaits further support. The mPFC and the orbitofrontal cortex (OFC) receive direct input from the amygdala (for an overview, see Barbas and Zikopoulos, 2006), whereas the lateral PFC
receives less, and mostly indirect, input via the cingulate or posterior OFC (Ray and Zald, 2012). Studies investigating amygdalaPFC connections in relation to anxiety have mostly focused on

Eden et al. Fiber Microstructure Predicts Anxiety Traits

J. Neurosci., April 15, 2015 35(15):6020 6027 6021

Table 1. Means and SDs of demographic, behavioral, and fractional anisotropy (in target regions) data, separately for both anxiety groups
FA
Trait anxiety group Trait anxiety score Reappraisal score Age

Years of schooling IQ

Low

27.08 2.43

27.75 6.03

25.38 3.67 13 0

High

57.58 4.65

23.04 6.52

26.92 5.99 13 0

OFC

115.17 13.06 L: 0.533 0.017

R: 0.541 0.017
107.00 25.11 L: 0.522 0.030
R: 0.527 0.017

vmPFC

dmPFC

dlPFC

L: 0.544 0.015
R: 0.541 0.014
L: 0.488 0.152
R: 0.531 0.013

L: 0.553 0.015
R: 0.554 0.012
L: 0.505 0.157
R: 0.519 0.112

L: 0.545 0.019
R: 0.541 0.012
L: 0.471 0.183
R: 0.508 0.111

L, Left hemisphere; R, right hemisphere.

specific and direct connections, such as to the insula or via the

uncinate fasciculus. They neglected indirect routes via long association fibers (Modi et al., 2013; Baur et al., 2013a,b).
Our aim was to investigate white matter alterations in persons
with high and low trait anxiety, along multiple pathways connecting amygdala and PFC. We collected diffusion-weighted magnetic resonance images and applied probabilistic tractography
(Behrens et al., 2007) to reconstruct all potential pathways between the amygdala and PFC regions associated with anxietyrelated processes. A rather large body of literature established an
association of anxiety with right-hemispheric activity (Davidson
et al., 1990), and thus we hypothesized trait anxiety to be associated with weaker right-hemispheric connections. Mechanisms of
reappraisal are less investigated, but there is some evidence for
left-hemispheric lateralization of reappraisal (Ochsner et al.,
2002) as well as higher metabolic activity in left frontal regions in
reappraisal users (Kim et al., 2012). Consequently, reappraisal
was expected to be associated with stronger left-hemispheric connections brought forth by intensive use.

Materials and Methods

Subjects
Three hundred ten nonclinical volunteers completed an on-line version
of the Spielberger Trait Anxiety Inventory (Spielberger et al., 1983). On
the basis of individual trait scores, right-handed (according to the Edinburgh Handedness Inventory; Oldfield, 1971) female participants were
selected if they scored 30 or 50. In a next step, they were matched for
age. This established two groups of participants (n 24 each), one with
low anxiety [LA; mean trait score, 27.08 (SD, 2.43); mean age, 25.38 (SD,
3.679)] and one with high anxiety [HA; mean trait score, 27.08 (SD,
2.43); mean age, 25.38 (SD, 3.67)], that did not differ for age (df 46,
T 1.414, p 0.166) nor years of schooling. All group members were
medically healthy and had no history of psychiatric medication or mental
disorders, as verified by the Mini International Neuropsychiatric Interview (version 5.0.0) of the Diagnostic Statistical ManualIV (Ackenheil
et al., 1999). The participants that were excluded from the two groups did
not fulfill one or more of the required inclusion criteria. All procedures
rztekammer Westfalenwere cleared by the ethical review board of the A
Lippe, and subjects gave informed consent for their participation.

Procedure
To control for intelligence differences between groups, the Wechsler
Adult Intelligence Scale (German version of the WAIS-III; Von Aster et
al., 2006) was administered individually to every subject 2 d before image
acquisition. No significant differences were found between the HA and
LA groups (HA: mean, 107.00; SD, 25.11; LA: mean, 115.17; SD, 13.06;
T 1.414, p 0.164). Participants completed the German version of the
Emotion Regulation Questionnaire (Gross and John, 2003), which measures reappraisal use. The two groups displayed significant differences in
reappraisal use (HA: mean, 23.04; SD, 6.52; LA: mean, 27.75; SD, 6.03;
T 2.598, p 0.013; see Table 1 for means separated by group).

Image acquisition
Participants were instructed to lie still and stay awake throughout the
entire scanning procedure. Diffusion MRI (dMRI) and structural T1weighted images were acquired on a 3T MR scanner (Intera 3.0T; Philips
Medical Systems), with an inner bore diameter of 60 cm, equipped with

Quasar-Dual Gradients with two modes, either 40 mT/m gradient

strength and 200 mT/m/ms slew rate for general imaging or 80 mT/m
gradient strength and 100 mT/m/ms slew rate for diffusion imaging.
Diffusion MRI. High-angular resolution dMRI data were acquired using a six-channel head coil with a single-shot spin echo EPI sequence (TE,
55 ms; TR, 15,623 ms; image matrix, 128 128; FOV, 240 240 mm 2),
providing 60 diffusion-encoding gradient directions with a b value of
1000 s/mm 2 and a single measurement without a diffusion-weighting
gradient (b 0 s/mm 2). Seventy-eight axial slices with 1.88 mm thickness were acquired in an interleaved manner, covering the whole brain.
This resulted in cubic voxels of 1.88 mm edge length. Parallel image
acquisition was applied using SENSE with an acceleration factor of 2 and
a scan duration of 20 min.
Anatomical MRI. The T1-weighted images were acquired with a 3D
nonequilibrium gradient echo sequence (turbo field echo) with waterselective excitation. Contrast preparation of magnetization consisted of a
nonselective inversion pulse every 1020 ms. Imaging parameters were as
follows: TR, 9.3 ms; final TE, 4.4 ms; pulse angle, 9; FOV, 300 239
234 mm 3 (foot-head anterior-posterior right-left); cubic voxels of 1.17
mm edge length; SENSE acceleration factor 2 scan duration, 8.43 min.

dMRI preprocessing
Before data processing, dMRI volumes that were corrupted by movement of the participants were removed from the datasets. First, an automatic method was used to remove volumes of low quality. The algorithm
is based on the fact that motion eliminates the signal in a slice when
motion occurs during its acquisition. Usually, the average voxel intensity
of two consecutive slices does not change much. Only when motion
extinguishes the signal in parts of a slice does its average voxel intensity
differ greatly from its neighbors and indicate corruption of the volume.
In a following control step, visual inspection of the datasets ensured the
satisfactory quality of the remaining data. The cleaned dMRIs were interpolated to 1 mm isotropic resolution, aligned with the MNI template,
and corrected for motion and eddy-current effects in one step with a
single interpolation. The diffusion tensor and the FA maps were computed by use of the FSL software package (http://fsl.fmrib.ox.ac.
uk/fsl/fsl-4.1.9; Smith et al., 2004; Woolrich et al., 2009; Jenkinson et al.,
2012).

Regions for connectivity analysis

Based on the literature, four regions in the PFC were defined: the ventromedial PFC (vmPFC; Buckholtz et al., 2008), the dorsomedial PFC
(dmPFC; Kim et al., 2011), the dorsolateral PFC (dlPFC; Stein et al.,
2007), and the OFC (Zald and Kim, 1996a,b; Rauch et al., 1997; Sladky et
al., 2012). Since the precise anatomical locations and boundaries of these
areas have not yet been defined beyond controversy (Roy et al., 2012),
there was no suitable ready-to-use atlas that comprised all four PFC areas
for our purposes. Thus, we manually created an atlas that included the
dmPFC, dlPFC, OFC, and vmPFC based on the atlas introduced by Oishi
(type II WMPM; Oishi et al., 2009). The ventral and dorsal regions were
separated by an axial cutting plane at z 5 (MNI). The posterior end of
the ROIs was defined at y 0 (MNI). This atlas was morphed on the
individual brains using nonlinear registration (Avants et al., 2008) obtained from a registration of the FA template (FMRIB58_FA_1 mm supplied with FSL) onto the individual FA map. Figure 1 illustrates the
defined PFC areas applied in this study. The amygdala regions were
obtained by registration of the combined population maps of the
amygdala parcellation (Solano-Castiella et al., 2010) to each individual

6022 J. Neurosci., April 15, 2015 35(15):6020 6027

Eden et al. Fiber Microstructure Predicts Anxiety Traits

FA map, and they were thresholded at a value

of 3. The average volumes of the left and right
amygdala were 1478 and 1586 mm 3,
respectively.

Analysis of white matter microstructure

Probabilistic tractography based on the balland-stick model (Behrens et al., 2007) that is
implemented in the FSL software package was
used to create the connectivity maps between
amygdala and the PFC regions. These connectivity maps indicate for every voxel by how
many probabilistic tracks it has been crossed.
One thousand tracks were started in every
voxel of the amygdala, but only those that
reached one of the prefrontal regions were considered. Starting a fixed number of tracks in Figure 1. A, Illustration of the manually created atlas applied in this study. B, Axial slice of one subject with one exemplary
every voxel of the amygdala masks leads to a probabilistic track that connects the amygdala with the prefrontal cortex. Voxels selected for the analysis (red) are located within
different number of probabilistic tracks in ev- the probabilistic track (green) and the individual skeleton and have FA values higher than 0.4.
ery subject, because of different sizes of indiwe expected the factor trait anxiety to explain most of the variance.
vidual amygdalae. To compensate for this effect, all voxel values in the
Hence, trait anxiety was the first to enter this regression, followed by
connectivity maps were normalized by dividing them by the volume of
reappraisal use and, finally, IQ. As above, we also tested the alternative
the individual amygdala. Tracks were only seeded in the amygdala and
model with reappraisal use as the first factor.
not in the PFC regions, as pilot testing revealed that only a very small
fraction of the tracks seeded in the PFC areas reached the amygdala so
that the statistical power of this testing was not sufficient.
Results
To evaluate differences in white matter coherence along the connectAfter an anatomical description of the fiber pathway connections
ing pathways, values of FA were compared between the groups. This was
between seed and target regions, the results of the statistical analachieved by a region-based analysis method (Snook et al., 2007; Faria et
yses of the FA values of these pathways will be reported.
al., 2010) that considered only voxels on the center line of the white
matter within the pathways defined by the connectivity maps. The central
Figure 2 shows the calculated pathways between the amygdala
line was defined by computing the skeleton of each individuals FA map
and the four target regions of the prefrontal cortex: the OFC, the
as implemented in the tract-based spatial statistics software package
vmPFC, the dmPFC, and the dlPFC, (see Table 1 for FA means
(TBSS, http://fsl.fmrib.ox.ac.uk/fsl/fslwiki/TBSS; Smith et al., 2006), takseparated by group). The calculated pathways of both hemiing into account only voxels with an FA value higher than 0.4 (Fig. 1B,
spheres did not show qualitative differences, so that the connecgreen). To define the target-specific ROI, the connectivity maps were
tions are exemplarily shown in the right hemisphere. The ventral
thresholded at a specific level for every target region. These levels were
PFC regions (Fig. 2 A, B) are connected with the amygdala via a
computed separately by averaging the 90% quantiles of all individual
direct ventral pathway following the uncinated fascicle. Addinormalized connectivity maps. The FA values on the skeleton within this
tionally, a strong indirect limbic connection was found. This
mask were averaged.

Amygdalaprefrontal pathways
The individual connectivity maps for each prefrontal connection were
normalized with the transformation obtained from the atlas registration,
averaged across participants, and thresholded at the target-specific level.
The anatomical locations of the fiber pathways were evaluated based on
the anatomical slices and a 3D volume rendering using the LIPSIA software (Lohmann et al., 2001).

Statistical analysis
To test the influence of trait anxiety and reappraisal use on the pathway
strength between amygdala (seed) and PFC regions (targets), multiple
hierarchical regressions were calculated individually for both hemispheres, with the factors trait anxiety (high trait anxiety vs low trait
anxiety, dummy coded), the individual reappraisal use score, and the
individual IQ score. The factor IQ was added to check the specificity of
the resultant pathways for emotion-related characteristics. There is evidence for a positive correlation between FA and IQ (Schmithorst et al.,
2005). If the delineated microstructure is emotion specific, IQ should not
explain additional variance.
The FA values on the calculated pathways between seed and targets
(dmPFC, dlPFC, vmPFC, and OFC, respectively) served as dependent
variables. Note that because of a priori knowledge of asymmetric hemispheric processing, we calculated hierarchical regressions and set up different hierarchies for both hemispheres. In the left hemisphere, the factor
reappraisal use was expected to explain most of the variance and thus was
the first variable to enter the regression, followed by the factor trait
anxiety and IQ as a third factor. To underline the hypothesis-driven
approach, we also tested the model where trait anxiety was the first factor.
Based on the literature, we expected no effects. In the right hemisphere,

pathway followed the fornix and the temporopulvinar tract to the

posterior thalamic nuclei, continuing through the anterior thalamic radiation to the frontal lobe. The latter connection was also
observed for the dorsal PFC regions (Fig. 2C,D). The dorsal regions and the vmPFC also showed a connection with the
amygdala via the cingulum.
Multiple hierarchical regressions
There are correlations between use of reappraisal and trait anxiety (r 0.377; p 0.008), but both of these variables did not
correlate with IQ (reappraisal: r 0.130, p 0.379; trait anxiety: r 0.182, p 0.216; all Pearson correlations). The intercorrelations between trait anxiety and reappraisal use stress the
use of methods that take this intercorrelation into account, such
as regression analysis.
The results of the multiple hierarchical regression analyses
with factor trait anxiety group as the first predictor (right hemisphere) will be reported first, followed by the results of the multiple hierarchical regression analyses with the factor reappraisal
use as the first predictor (left hemisphere).
The factor trait anxiety group (high trait anxiety vs low trait
anxiety) significantly predicted the FA values on the white matter
microstructure between the amygdala and the vmPFC (r 0.350,
df 47, F 6.441, T 2.538, p 0.015) and between the
amygdala and the OFC (r 0.395, df 47, F 8.520, T
2.919, p 0.005), both in the right hemisphere (see Table 2 for
a list of all statistical parameters for all multiple hierarchical re-

Eden et al. Fiber Microstructure Predicts Anxiety Traits

J. Neurosci., April 15, 2015 35(15):6020 6027 6023

Figure 2. AD, Left, Three-dimensional sagittal and superior views of tracts between amygdala and PFC regions: A, orbitofrontal cortex; B, ventromedial PFC; C, dorsomedial PFC; D, dorsolateral
PFC. Renderings show the normalized number of tracts through each voxel (red). Seed and target regions are displayed in blue. For normalization, each voxel was divided by the amygdalas size. E,
Slices illustrating the tracts localization from medial to lateral. The distance between slices is 5 mm.

gressions). The FA values on the right-hemispheric white matter

microstructure between the amygdala and the dmPFC (r 0.215,
df 47, F 2.240, T 1,497, p 0.141) or the dlPFC (r
0.209, df 47, F 2.097, T 1,448, p 0.154) could not

significantly be predicted. In line with our hypotheses, the factor

reappraisal did not explain additional variance in this hemisphere
(vmPFC: r 0.377, df 47, F 3.731, T 1.009, p 0.318;
OFC: r 0.397, df 47, F 4.209, T 0.266, p 0.792;

Eden et al. Fiber Microstructure Predicts Anxiety Traits

6024 J. Neurosci., April 15, 2015 35(15):6020 6027

Table 2. Significant relationships between trait anxiety, reappraisal use, IQ, and
fractional anisotropy values of pathway microstructure between amygdala and
prefrontal cortex regions
ROI

Model

R2

Cor. R 2

TA

Right dmPFC

TA
TA, R
TA, R, IQ
R
TA
TA, R
TA, R, IQ
R
TA
TA, R
TA, R, IQ
R
TA
TA, R
TA, R, IQ
R
R
R, TA
R, TA, IQ
TA
R
R, TA
R, TA, IQ
TA
R
R, TA
R, TA, IQ
TA
R
R, TA
R, TA, IQ
TA

0.05
0.06
0.06
0.03
0.04
0.06
0.06
0.04
0.12
0.14
0.18
0.07
0.16
0.16
0.17
0.01
0.09
0.11
0.11
0.05
0.11
0.14
0.15
0.08
0.11
0.13
0.14
0.06
0.09
0.11
0.15
0.05

0.03
0.02
0.00
0.01
0.02
0.02
0.00
0.02
0.10
0.10
0.13
0.05
0.14
0.12
0.11
0.01
0.07
0.07
0.05
0.03
0.09
0.10
0.09
0.06
0.09
0.09
0.08
0.04
0.07
0.07
0.09
0.03

2.24
1.41
0.95
1.56
2.10
1.53
1.01
2.06
6.44*
3.73*
3.31*
3.21
8.52**
4.21*
2.92*
0.54
4.74*
2.69
1.87
2.27
5.85*
3.73*
2.52
3.91
5.65*
3.36*
2.29
3.13
4.59*
2.68
2.51
2.44

0.22
0.17
0.18

Right dlPFC

Right vmPFC

Right OFC

Left dmPFC

Left dlPFC

Left vmPFC

Left OFC

0.21
0.16
0.16
0.35*
0.30
0.34*
0.40**
0.41**
0.39*
0.12
0.14
0.22
0.18
0.20
0.28
0.15
0.17
0.25
0.13
0.17
0.22

IQ

0.12
0.12
0.18

0.05

0.15
0.15
0.21

0.02

0.15
0.16
0.26

0.21

0.04
0.04
0.11
0.31*
0.26
0.27

0.08

0.34*
0.27
0.28

0.07

0.33*
0.28
0.28

0.07

0.30*
0.25
0.27

0.20

0.10

Model parameters for each predictor variable for hierarchical regression analyses are shown. Dependent variables
are fractional anisotropy values of pathway microstructure between amygdala and prefrontal cortex regions. ROI,
Region of interest; TA, trait anxiety; R, reappraisal use. *p 0.05; **p 0.01.

dmPFC: r 0.242, df 47, F 1.405, T 0.769, p 0.446;

dlPFC: r 0.252, df 47, F 1.530, T 0.982, p 0.331) and
IQ (vmPFC: r 0.429, df 47, F 3.308, T 1.502, p
0.140; OFC: r 0.408, df 47, F 2.923, T 0.674, p 0.504;
dmPFC: r 0.247, df 47, F 0.953, T 0.322, p 0.749;
dlPFC: r 0.253, df 47, F 1.005, T 0.148, p 0.883). As
expected, the alternative model with reappraisal as first factor did
not become significant in any of the four (right-hemispheric)
analyses.
The factor reappraisal significantly predicted the FA values
on the calculated white matter microstructure between the
amygdala and all four predefined PFC regions in the left hemisphere (dmPFC: r 0.306, df 47, F 4.741, T 2.177, p
0.035; dlPFC: r 0.336, df 47, F 5.854, T 2.419, p 0.020;
vmPFC: r 0.331, df 47, F 5.652, T 2.377, p 0.022;
OFC: r 0.301, df 47, F 4.591, T 2.143, p 0.037). The
addition of the factor anxiety group did not significantly increase
the explanation of variance in any of the regions (dmPFC: r
0.327, df 47, F 2.686, T 0.816, p 0.419; dlPFC: r
0.377, df 47, F 3.727, T 1.238, p 0.222; vmPFC:
r 0.361, df 47, F 3.364, T 1.033 p 0.307; OFC: r
0.326, df 47, F 2.678, T 0.887, p 0.380) or IQ (dmPFC:
r 0.336, df 47, F 1.870, T 0.564, p 0.576; dlPFC: r
0.383, df 47, F 2.521, T 0.485, p 0.630; vmPFC: r
0.367, df 47, F 2.285, T 0.491, p 0.626; OFC: r 0.382,

df 47, F 2.512, T 1.433, p 0.159). As hypothesized, the

alternative model with trait anxiety entering as first factor did not
reveal any effects.

Discussion
We investigated the microstructural properties of pathway connections between the amygdala and PFC regions deemed relevant
for anxiety and emotion regulation. The results provide direct
evidence for stronger connectivity between amygdala and
vmPFC and OFC of the right hemisphere in persons with low
trait anxiety. Emotion regulation was expressed as stronger connectivity between amygdala and vmPFC, OFC, dmPFC, and
dlPFC of the left hemisphere in persons with high reappraisal use.
We collected diffusion-weighted images (dMRI) and applied
probabilistic tractography to compute all tracks between
amygdala and PFC regions individually for both hemispheres.
The resulting white matter circuitry included (parts of) the uncinate fasciculus, cingulum, fornix, anterior thalamic radiation,
and inferior fronto-occipital fasciculus. Strong connectivity via
the uncinate fasciculus was observed for the pathways to vmPFC
and OFC, which was neither seen in the pathway network to
dlPFC nor to dmPFC. These connections, especially to vmPFC,
fit with findings from dMRI studies on humans and animals
(Croxson et al., 2005; Carlson et al., 2013; Jbabdi et al., 2013) and
with anatomical studies that reported extensive anatomical connections between the amygdala and the PFC. For instance, in rats
and monkeys, it was shown that the amygdala is connected to
prefrontal cortex by direct amygdalo-cortical projections (Nauta,
1961; Krettek and Price, 1974, 1977a), and indirectly via the thalamus (Nauta, 1962; Krettek and Price, 1974, 1977a,b). In rhesus
monkeys, the ventromedial region of PFC receives both direct
and indirect tracts stemming from the amygdala, but the dorsolateral PFC does not get such input (Porrino et al., 1981). These
findings suggested that the ventromedial region may be regarded
as the limbic portion of the frontal association cortex. The
longer, presumably indirect routes found in our study have not
been focused on and rarely have been addressed in human dMRI
studies on emotion processing or anxiety. Reviewing the role of
the PFC in emotion cognition interactions, Ray and Zald (2012)
emphasized that studies on nonhuman primates reveal large variability concerning direct projections between the amygdalae and
regions of the PFC and that direct projections between amygdala
and dlPFC are extremely weak. It may thus be surprising that
we find such strong connections between amygdala and prefrontal regions. However, there is ample evidence for indirect pathways, most notably through the thalamus, in both animals and
humans.
Recent research using tractography in humans provided further evidence for strong connections between hippocampus/
amygdala and thalamus. The amygdala connects with the
anterior thalamus via the fornix and uncinate fasciculus and with
the pulvinar via the temporopulvinar tract (Zarei et al., 2010).
Similarly, Linke et al. (2012) reported indirect pathways from the
amygdala to the OFC, namely via the anterior and posterior thalami. Note that these studies did not specifically target the connection between the amygdala and prefrontal regions.
With multiple hierarchical regressions, we analyzed the relationship of these determined fiber connections with trait anxiety
and reappraisal use by means of hypothesis-driven, hemispherespecific models. Given accumulating evidence for an asymmetric
involvement of the PFC, with a right-hemispheric dominance for
anxiety and anxiety-related processes (Stewart et al., 1988; Hermann et al., 1992; Hellige, 1993; OCarroll et al., 1993; Petruzzello

Eden et al. Fiber Microstructure Predicts Anxiety Traits

and Landers, 1994; Lucey et al., 1995; Stapleton et al., 1997; Bremner et al., 1999; Nitschke et al., 1999; Wiedemann et al., 1999;
Davidson et al., 2000; Davidson, 2002; Pizzagalli et al., 2002; Smit
et al., 2007, Harmon-Jones et al., 2010), we expected our structural trait anxiety effects to be particularly visible in the right
hemisphere. Based on evidence for a left-hemispheric lateralization of reappraisal use (Ochsner et al., 2002; Jackson et al., 2003;
Kim and Bell, 2006) and recently observed left-sided biases of
metabolic activity in the superior frontal gyrus in frequent reappraisers (Kim et al., 2012), we expected reappraisal use effects to
be most prominent in the left hemisphere. We set up the hierarchies of the multiple regression analysis accordingly, with trait
anxiety as the first factor in the analyses of the right hemisphere
and with reappraisal use as the first factor for the left hemisphere.
The following methodological details are important to consider. First, we chose a hypothesis-based approach, analyzing the
microstructure of only those tracts to PFC regions that have consistently been associated with emotion-related processes. Different from prior studies, all tracks, including longer pathways
between the two structures, were considered. We calculated the
tracts for subsequent FA analysis on our sample, not relying on
data from thematically different experimental contexts. This is
more conservative than a whole-brain approach, where significant
regions are selected, analyzed, and interpreted post hoc. Second, we
also adopted the hypothesis-based approach in the statistical analysis. As mentioned above, anxiety and use of reappraisal is related to
hemisphere-specific networks. Whereas anxiety is primarily (but not
exclusively) related to processes of right-hemispheric amygdala and
PFC (Reiman et al., 1984; Heller et al., 1995), emotion regulation is
primarily associated with left-hemispheric processing in these
structures (Wheeler et al., 1993; Jackson et al., 2003; Kim and Bell,
2006; Kim et al., 2012). This differential hemispheric involvement in different aspects of emotion processing and regulation
supports the hypotheses by Davidson and colleagues (Davidson
et al., 1987, 1990, 2000; Davidson and Tomarken, 1989; Davidson, 1992, 1995, 2002; Sutton and Davidson, 1997). In low traitanxious persons, there was no higher FA in pathways to the
dorsomedial and the dorsolateral part of the PFC. One reason
might be that the amygdalar inhibition by these PFC regions
operates via general mechanisms, such as changes in the neurotransmitter system. Such mechanisms might not be reflected in
FA values of connecting pathways (Ray and Zald, 2012). An alternative explanation is that our atlas comprised comparably
wide boundaries around the dmPFC and the dlPFC. Although
this was deliberately done as not to miss potentially important
fibers, it could have led to an attenuation of the expected effect.
Some caveats and open questions should be addressed in future studies. First, we probabilistically tracked fiber pathways
from amygdala to PFC within each hemisphere, focusing on noncrossing fibers. However, animal studies have shown that a small
percentage of connecting fibers between the amygdala and the
PFC crosses the corpus callosum (Mascagni et al., 1993; McDonald and Mascagni, 1996). A second caveat concerns the origin of
the calculated fibers within the amygdala. We mapped the
amygdala in each participant and treated the entire amygdala as
seed region. Yet, the amygdala is a heterogeneous structure, with
various substructures and nuclei (Sah et al., 2003), each with
different functions and connections with different areas in the
brain. It is thus a challenge for future DTI studies to differentiate
connections between amygdala substructures and regions of the
PFC. Third, because women are especially prone to develop anxiety disorders (see Somers et al., 2006) and to avoid additional
variance attributable to existing brain-activation differences be-

J. Neurosci., April 15, 2015 35(15):6020 6027 6025

tween men and women (Gong et al., 2011), we included only

female persons. Studies revealed the sexually dimorphic nature of
the cortex, limbic structures, and connecting fibers and how such
sex differences might impact the development of affective disorders (for review, see Cahill, 2006). Zuurbier et al. (2013) observed
correlations between reappraisal and FA values in the left frontal
part of uncinate fasciculus in women, but not in men. Thus, it is
likely that at least some of the connections between amygdala and
PFC reported here cannot easily be transferred to men.
Although our results have to be interpreted within the constraints of the above-mentioned limitations, we believe that our
data make an important contribution to the understanding of the
neuroanatomical basis of anxiety and emotion regulation. Our
findings provide strong support for theories of and (fMRI) studies on top-down inhibition, by offering a structural network that
might underlie the so far mostly theoretically, behaviorally, and
functionally argued/established network.
Our data show that different structural networks are responsible for trait anxiety and reappraisal use. Neural models on the
generation and regulation of emotions stress the importance of
the interplay between automatic and voluntary processes (e.g.,
use of reappraisal; Ochsner and Gross, 2007; Phillips et al., 2008)
and emphasize the role of the amygdala and PFC regions (particularly OFC) for this interplay. The attempt to study voluntary
and automatic processes in separation may seem futile (Phillips et
al., 2008), especially in therapeutic settings. Nevertheless, we
identified a hemispherically specialized functional architecture
involved in the mediation of anxiety and reappraisal use, with
stronger connectivity between amygdala, OFC, and vmPFC in
each hemisphere. Given the correlational nature of these data, we
cannot make claims about the development of the relationship. It
is a challenge for future research to investigate how manipulating
one of these processes [e.g., using the anxiolytic effects of noninvasive brain stimulation (Zwanzger et al., 2009)] impacts on the
other, especially on the microstructure involved. Such investigations might help to develop new strategies for the treatment of
anxiety disorders and to identify persons at risk.

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